Experimental evidence points to placebo responses that can potentially enhance, as well as confound, the therapeutic benefit of active conditions. Perhaps the area in which the effects of placebos have been best described at pharmacological and behavioral levels is that involving experimental and clinical pain. Expectation of analgesia during placebo administration activates endogenous opioid neurotransmitter systems, in turn regulating sensory and affective qualities of pain. However, at the present time the neuronal and neurochemical networks where placebo-associated sensory, emotional and cognitive appraisals are translated into neurobiological effects are unknown. The endogenous opioid system is known to suppress stress responses and pain through the activation of mu-opioid receptors. Recent data from our laboratory has demonstrated that this regulation takes place at multiple brain levels, including cortical and subcortical regions involved in the integration of sensory, emotional and cognitive information (anterior cingulate, prefrontal cortex, insular cortex, thalamus, nucleus accumbens, amygdala). This information, together with that arising from biobehavioral studies suggests that/mu-opioid mechanisms impacting integrative-motivational brain networks may be mediating the "mind-body" interactions typically associated with placebo responses. In this regard, preliminary data is presented demonstrating the susceptibility of this neurotransmitter system to modulation by cognitive-emotional appraisals, including the expectation of a pain stressor. The present proposal seeks to examine the effects of a placebo intervention with expectation of analgesia on/mu-opioid neurotransmission, directly in human subjects with PET and molecular imaging techniques. Placebo responses are to be studied in healthy male and female volunteers during non-painful (saline control) and painful (sustained pain-stress challenge) conditions. We further control for factors known to influence the function of/mu-opioid networks: anticipatory stress responses, age, gender, and the female gonadal steroid environment. Knowledge of the circuits and mechanisms engaged in the production of placebo analgesia opens the possibility of designing scientifically-based methods to hamess those effects. Furthermore, examination of factors that regulate these placebo-activated neurotransmitter responses will greatly clarify the overall neurobiology underlying interindividual variations in the responses to placebos, as well as pain and other stressful conditions, ultimately leading to the optimization of medical and psychological interventions.